The present invention is directed to polyhydroxylated monocyclic N-heterocyclic derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anticoagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin .which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the xe2x80x9cXa burstxe2x80x9d pathway and by the factor IXa-VIIIa complex (TENase) of the xe2x80x9csustained Xaxe2x80x9d pathway in the coagulation cascade. After vessel injury, the xe2x80x9cXa burstxe2x80x9d pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the xe2x80x9csustained Xaxe2x80x9d pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the xe2x80x9cXa burstxe2x80x9d pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique xe2x80x9ctethered ligandxe2x80x9d thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anticoagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anticoagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
Related Disclosures
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of xcex1,xcex1xe2x80x2-bis(amidinobenzylidene)cycloalkanones and xcex1,xcex1xe2x80x2-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
U.S. Pat. No. 5,451,700 (Morrissey et al.) describes amidino compounds. These compounds are stated to be useful as selective LTB4 receptor antagonists.
U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/96/28427 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/21437 (Arnaiz et al.) describes naphthyl-substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/29067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
The above references, published patent applications and U.S. patents are herein incorporated in full by reference.
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of desease-states characterized by thrombotic activity.
Accordingly, in one aspect, this invention provides compounds selected from the group consisting of the following formulae: 
wherein:
A is xe2x80x94C(R8)xe2x95x90 or xe2x80x94Nxe2x95x90 (where R8 is hydrogen, alkyl or halo);
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94N(R9)xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94(where n is 0 to 2);
Z2 is xe2x80x94Oxe2x80x94, xe2x80x94N(R9)xe2x80x94, xe2x80x94OCH2xe2x80x94 or S(O)nxe2x80x94(where n is 0 to 2);
R1 and R4 are each independently hydrogen, halo, alkyl, nitro, xe2x80x94OR9, xe2x80x94C(O)OR9, xe2x80x94C(O)N(R9)R10, xe2x80x94N(R9)R10, N(R9)C(O)R9, or xe2x80x94N(H)S(O)2R11;
R2 is xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)OR9, xe2x80x94C(NH)N(H)C(O)OR11, xe2x80x94C(NH)N(H)C(O)R9, xe2x80x94C(NH)N(H)S(O)2R11, or xe2x80x94C(NH)N(H)C(O)N(H)R9;
R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, xe2x80x94OR9, xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)OR9, xe2x80x94C(O)N(R9)R10, R12xe2x80x94C(O)N(R9)R10, xe2x80x94CH(OH)C(O)N(R9)R10, xe2x80x94N(R9)R10, xe2x80x94R12xe2x80x94N(R9)R10, xe2x80x94C(O)OR9, xe2x80x94R12xe2x80x94C(O)OR9, xe2x80x94N(R9)C(O)R9, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, xe2x80x94N(R9)R10, xe2x80x94C(O)OR9, xe2x80x94C(O)N(R9)R10, xe2x80x94C(O)N(R9)CH2C(O)N(R9)R10, xe2x80x94N(R9)C(O)N(R9)R10, xe2x80x94N(R9)C(O)R10, xe2x80x94N(R9)S(O)2R11, or xe2x80x94N(R9)C(O)N(R9)xe2x80x94CH2C(O)N(R9)R10;
R7 is xe2x80x94Xxe2x80x94CH2xe2x80x94[C(R13)H]pxe2x80x94C(R13)H2 or xe2x80x94Xxe2x80x94C([C(R13)H]pxe2x80x94C(R13)H2)2H where:
p is 0 to 5;
X is xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2), or xe2x80x94N(R9)xe2x80x94; and each R13 is independently xe2x80x94[C(OR9)H]mxe2x80x94CH2xe2x80x94OR9 (where m is 1 to 4), xe2x80x94[CH2]nxe2x80x94OR9, xe2x80x94[CH2]nxe2x80x94SR9, xe2x80x94[CH2]nxe2x80x94N(R9)R10, xe2x80x94[CH2]nxe2x80x94OC(O)R9, xe2x80x94[CH2]nxe2x80x94SC(O)R9, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)R9, xe2x80x94[CH2]nxe2x80x94OC(O)OR11, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)OR11, xe2x80x94[CH2]nxe2x80x94OC(O)N(R9)R10, or xe2x80x94[CH2]nxe2x80x94N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
or R7 is selected from the group consisting of the following formulae: 
where
q is 0 to 4;
p is 0 to 5;
each R13 is independently xe2x80x94[C(OR9)H]mxe2x80x94CH2xe2x80x94OR9 (where m is 1 to 4), xe2x80x94[CH2]nxe2x80x94OR9, xe2x80x94[CH2]nxe2x80x94SR9, xe2x80x94[CH2]nxe2x80x94N(R9)R10, xe2x80x94(CH2)nxe2x80x94OC(O)R9, xe2x80x94[CH2]nxe2x80x94SC(O)R9, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)R9, xe2x80x94[CH2]nxe2x80x94OC(O)OR11, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)OR11, xe2x80x94[CH2]nxe2x80x94OC(O)N(R9)R10, or xe2x80x94[CH2]nxe2x80x94N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2); and
each R14 is xe2x80x94Xxe2x80x94[CH2]xe2x80x94, or xe2x80x94Xxe2x80x94CH2xe2x80x94[C(R13)H]rxe2x80x94, where:
each r is independently 0 to 5, and
each X is xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94(where n is 0 to 2), or xe2x80x94N(R9)xe2x80x94; and
each R13 is independently xe2x80x94[CH(OR9)]mxe2x80x94CH2xe2x80x94OR9 (where m is 1 to 4), xe2x80x94[CH2]nxe2x80x94OR9, xe2x80x94[CH2]nxe2x80x94SR9, xe2x80x94[CH2]nxe2x80x94N(R9)R10, xe2x80x94[CH2]nxe2x80x94OC(O)R9, xe2x80x94[CH2]nxe2x80x94SC(O)R9, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)R9, xe2x80x94[CH2]nxe2x80x94OC(O)OR11, xe2x80x94[CH2]nxe2x80x94N(R9)C(O)OR11, xe2x80x94[CH2]nOC(O)N(R9)R10, or xe2x80x94[CH2]nxe2x80x94N(R9)C(O)N(R9)R10 (where each n is independently 0 to 2);
each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
each R11 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); and
each R12 is independently an alkylene or alkylidene chain;
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides compositions useful in treating a human having a desease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, this invention provides a method of treating a human having a desease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of the invention.